DOE OSTI · 3374411
Beyond sequence similarity: toward function-based screening of nucleic acid synthesis
Abstract
Synthetic nucleic acids are a key input to modern biotechnology, yet they represent dual-use materials that require robust screening to mitigate biosecurity risks. The prevailing screening paradigm, which identifies sequences of concern (SoCs) through sequence similarity to controlled pathogens and toxins, may not fully capture risks posed by AI tools that can decouple biomolecular function from reliance on known sequences. Rapidly advancing biodesign capabilities enable the generation of genes and proteins that might evade sequence-based detection. We highlight the critical need for function-based screening approaches that can detect sequences capable of hazardous biological functions, regardless of similarity to known SoCs. We examine the feasibility of function-based screening with an initial focus on proteins, arguing that, while protein sequence space is vast, biologically functional proteins are significantly constrained by biophysical and biochemical requirements that can be learned and modeled. We propose a concrete implementation framework organized along a continuum of complexity, starting with toxins as the most tractable targets before expanding to more complex pathogenic functions. We then discuss open challenges and describe a research and development strategy to address them.
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Abel, Jr., Gary R. [Fourth Eon Bio, San Diego, CA (United States); Johns Hopkins Univ., Baltimore, MD (United States)], Alexanian, Tessa [International Biosecurity and Biosafety Initiative for Science (IBBIS), Geneva (Switzerland)], Bartling, Craig [Battelle Memorial Institute, Columbus, OH (United States)], Beal, Jacob [RTX BBN Technologies, Cambridge, MA (United States)], Curtis, Samuel [National Institute of Standards and Technology (NIST), Washington, DC (United States). Center for AI Standards and Innovation (CAISI)], Flyangolts, Kevin [Aclid, New York, NY (United States)], Foner, Leonard [SecureDNA, Basel (Switzerland)], Forry, Samuel P. [National Institute of Standards and Technology (NIST), Gaithersburg, MD (United States)], Godbold, Gene D. [Signature Science LLC, Charlottesville, VA (United States)], Horvitz, Eric [Microsoft Corporation, Redmond, WA (United States)], Hu, Bin [Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)] (ORCID:0000000202788466), Hudson, Corey M. [The Align Foundation, Covina, CA (United States)], Jagla, Caitlin [RTX BBN Technologies, Cambridge, MA (United States)], Lababidi, Rassin [International Biosecurity and Biosafety Initiative for Science (IBBIS), Geneva (Switzerland)], Lin-Gibson, Sheng [National Institute of Standards and Technology (NIST), Gaithersburg, MD (United States)], Magalis, Brittany Rife [Univ. of Louisville, KY (United States)], Pannu, Jaspreet [Johns Hopkins Univ., Baltimore, MD (United States)], Rivera, Sebastian [Engineering Biology Research Consortium, Emeryville, CA (United States)], Ross, David [National Institute of Standards and Technology (NIST), Gaithersburg, MD (United States)], Wittmann, Bruce J. [Microsoft Corporation, Redmond, WA (United States)], Diggans, James [Twist Bioscience, San Francisco, CA (United States); International Gene Synthesis Consortium, Emeryville, CA (United States)]. 2026-05-14. Beyond sequence similarity: toward function-based screening of nucleic acid synthesis. https://doi.org/10.3389/fbioe.2026.1832724
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